It is well established that aging is reflected in morphologic and functional change in the immune system. This change is particularly reflected in the decreased responsiveness of the T-cell component of this system and is evidenced by decreased proliferation responses to activation signals received and transmitted through T-cell receptor activation pathways. In addition, age-related changes occur in T-cell subpopulations, as determined by their phenotypic markers. These subpopulations have different roles in the generation of an immune response and these roles relate to their functional capabilities and production of chemical mediators, such as cytokines. While numerous studies have examined age-related decrease in T-cell response and focussed on important alterations in various activation pathway components, few studies have been able to identify the major underlying genetic regulatory mechanisms. The goal of this project is to initiated a study that will take advantage of the shuffling of the genetic backgrounds from two inbred mouse strains in a unique animal model system-the recombinant inbred (RI) mouse. These studies will be accomplished by the identification of genes with a major influence on age-related changes in the T-cell proliferative response. To do this we propose to use the rapidly expanding definition of the components of the mouse genome and the quantitative trait loci (QTL) analysis of a series of 22 RI mouse strains and F2s derived from the C57BL/6(B6) and DBA/2(D2) parental mouse strains. Loci associated with strain and age-related differences in the T-cell proliferative response will be nominated in the RIs and confirmed in the F2 animals. Ultimately, fine mapping and gene cloning will enable specific characterization and identification of specific products that have a major role in age-associated immune system changes.